Mucosal and systemic immunity may be important for vaccines designed to prevent Trypanosoma cruzi and other mucosally invasive intracellular pathogens, but it is unknown whether optimal mucosal and systemic immunity can be induced concurrently. CD4+ Th1 cells (secreting IL-2, IFN-gamma and TNF-alpha) are important for systemic protection against intracellular pathogens. CD4+ Th2 cells (secreting IL-4, IL-5, IL-6 and IL-10) induce secretory IgA, protective against mucosal pathogens. However, reciprocal inhibitory actions between TH1 and Th2 cells exist. In addition, mucosal antigen delivery can induce immune tolerance associated with clonal deletion, anergy, or the induction of suppressor "Th3" cells secreting high levels of TGF-Beta. It is of critical importance to the field of vaccine immunobiology to further define the interactions between mucosal and systemic immunity against mucosally invasive intracellular pathogens. We propose to investigate the relationships between mucosal and systemic T. cruzi immunity as a model system for studying these interactions. First, we will address the hypothesis that protective immunity induced by T. cruzi infection involves different molecular and cellular immune requirements in mucosal and systemic tissues. The importance of total B cells, IgA, class I and II restricted T cells, IFN-gamma, IL-4 and inducible nitric oxide synthase will be studied in BALB/c mice and mice with targeted disruptions in these immune functions. Second, we will study the hypothesis that vaccines inducing differential CD4+ Th1 and Th2 responses will have different effects on mucosal and systemic protection. Vaccines including T. cruzi antigens and cytokine adjuvants will be studied for protective effects against mucosal and systemic challenges. Third, we will study the hypothesis that recombinant BCG salmonella vaccines expressing T. cruzi antigens in both mucosal and systemic tissues can induce concurrent mucosal and systemic protection. Protective soluble protein and live recombinant vaccines will be studied in genetic knockout mice to identify the molecular and cellular requirements for immune protection.